AndroGel 1.62

CLINICAL PHARMACOLOGY

Mechanism of Action

Endogenous androgens, including testosterone and dihydrotestosterone (DHT),
are responsible for the normal growth and development of the male sex organs
and for maintenance of secondary sex characteristics. These effects include
the growth and maturation of prostate, seminal vesicles, penis and scrotum;
the development of male hair distribution, such as facial, pubic, chest and axillary hair; laryngeal enlargement; vocal chord thickening; and alterations
in body musculature and fat distribution. Testosterone and DHT are necessary
for the normal development of secondary sex characteristics. Male hypogonadism
results from insufficient secretion of testosterone and is characterized by
low serum testosterone concentrations. Signs/symptoms associated with male hypogonadism
include erectile dysfunction and decreased sexual desire, fatigue and loss of
energy, mood depression, regression of secondary sexual characteristics and
osteoporosis.

Male hypogonadism can present as primary hypogonadism caused by defects of
the gonads, such as Klinefelter's Syndrome or Leydig cell aplasia while secondary
hypogonadism is the failure of the hypothalamus or pituitary to produce sufficient
gonadotropins (FSH, LH).

Pharmacodynamics

No specific pharmacodynamic studies were conducted using AndroGel 1.62%.

Figure 2: Mean (±SD) Serum Total Testosterone Concentrations
on Day 7 in Patients Following AndroGel 1.62% Once-Daily Application of 81 mg
of Testosterone (N=33) for 7 Days

Distribution

Circulating testosterone is primarily bound in the serum to sex hormone-binding
globulin (SHBG) and albumin. Approximately 40% of testosterone in plasma is
bound to SHBG, 2% remains unbound (free) and the rest is loosely bound to albumin
and other proteins.

Metabolism

Testosterone is metabolized to various 17-keto steroids through two different
pathways. The major active metabolites of testosterone are estradiol and DHT.

Excretion

There is considerable variation in the half-life of testosterone concentration
as reported in the literature, ranging from 10 to 100 minutes. About 90% of
a dose of testosterone given intramuscularly is excreted in the urine as glucuronic
acid and sulfuric acid conjugates of testosterone and its metabolites. About
6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation
of testosterone occurs primarily in the liver.

When AndroGel 1.62% treatment is discontinued, serum testosterone concentrations
return to approximately baseline concentrations within 48-72 hours after administration
of the last dose.

Potential for testosterone transfer

The potential for testosterone transfer following administration of AndroGel
1.62% when it was applied only to upper arms/shoulders was evaluated in two
clinical studies of males dosed with AndroGel 1.62% and their untreated female
partners. In one study, 8 male subjects applied a single dose of AndroGel 1.62%
81 mg to their shoulders and upper arms. Two (2) hours after application, female
subjects rubbed their hands, wrists, arms, and shoulders to the application
site of the male subjects for 15 minutes. Serum concentrations of testosterone
were monitored in female subjects for 24 hours after contact occurred. After
direct skin-to-skin contact with the site of application, mean testosterone
Cavg and Cmax in female subjects increased by 280% and 267%, respectively, compared
to mean baseline testosterone concentrations. In a second study evaluating transfer
of testosterone, 12 male subjects applied a single dose of AndroGel 1.62% 81
mg to their shoulders and upper arms. Two (2) hours after application, female
subjects rubbed their hands, wrists, arms, and shoulders to the application
site of the male subjects for 15 minutes while the site of application was covered
by a t-shirt. When a t-shirt was used to cover the site of application, mean
testosterone Cavg and Cmax in female subjects increased by 6% and 11%, respectively,
compared to mean baseline testosterone concentrations.

A separate study was conducted to evaluate the potential for testosterone transfer
from 16 males dosed with AndroGel 1.62% 81 mg when it was applied to abdomen
only for 7 days, a site of application not approved for AndroGel 1.62%. Two
(2) hours after application to the males on each day, the female subjects rubbed
their abdomens for 15 minutes to the abdomen of the males. The males had covered
the application area with a T-shirt. The mean testosterone Cavg and Cmax in
female subjects on day 1 increased by 43% and 47%, respectively, compared to
mean baseline testosterone concentrations. The mean testosterone Cavg and Cmax
in female subjects on day 7 increased by 60% and 58%, respectively, compared
to mean baseline testosterone concentrations.

Effect of showering

In a randomized, 3-way (3 treatment periods without washout period) crossover
study in 24 hypogonadal men, the effect of showering on testosterone exposure
was assessed after once daily application of AndroGel 1.62% 81 mg to upper arms/shoulders
for 7 days in each treatment period. On the 7th day of each treatment period,
hypogonadal men took a shower with soap and water at either 2, 6, or 10 hours
after drug application. The effect of showering at 2 or 6 hours post-dose on
Day 7 resulted in 13% and 12% decreases in mean Cavg, respectively, compared
to Day 6 when no shower was taken after drug application. Showering at 10 hours
after drug application had no effect on bioavailability. The amount of testosterone
remaining in the outer layers of the skin at the application site on the 7th
day was assessed using a tape stripping procedure and was reduced by at least
80% after showering 2-10 hours post-dose compared to on the 6th day when no
shower was taken after drug application.

Effect of sunscreen or moisturizing lotion on absorption of testosterone

In a randomized, 3-way (3 treatment periods without washout period) crossover
study in 18 hypogonadal males, the effect of applying a moisturizing lotion
or a sunscreen on the absorption of testosterone was evaluated with the upper
arms/shoulders as application sites. For 7 days, moisturizing lotion or sunscreen
(SPF 50) was applied daily to the AndroGel 1.62% application site 1 hour after
the application of AndroGel 1.62% 40.5 mg. Application of moisturizing lotion
increased mean testosterone Cavg and Cmax by 14% and 17%, respectively, compared
to AndroGel 1.62% administered alone. Application of sunscreen increased mean
testosterone Cavg and Cmax by 8% and 13%, respectively, compared to AndroGel
1.62% applied alone.

Clinical Studies

Clinical Trials in Hypogonadal Males

AndroGel 1.62% was evaluated in a multi-center, randomized, double-blind, parallel-group,
placebo-controlled study (182-day double-blind period) in 274 hypogonadal men
with body mass index (BMI) 18-40 kg/m² and 18-80 years of age (mean age
53.8 years). The patients had an average serum testosterone concentration of
< 300 ng/dL, as determined by two morning samples collected on the same visit.
Patients were Caucasian 83%, Black 13%, Asian or Native American 4%. 7.5% of
patients were Hispanic.

Patients were randomized to receive active treatment or placebo using a rotation
method utilizing the abdomen and upper arms/shoulders for 182 days. All patients
were started at a daily dose of 40.5 mg (two pump actuations) AndroGel 1.62%
or matching placebo on Day 1 of the study. Patients returned to the clinic on
Day 14, Day 28, and Day 42 for predose serum total testosterone assessments.
The patient's daily dose was titrated up or down in 20.25 mg increments if the
predose serum testosterone value was outside the range of 350-750 ng/dL. The
study included four active AndroGel 1.62% doses: 20.25 mg, 40.5 mg, 60.75 mg,
and 81 mg daily.

The primary endpoint was the percentage of patients with Cavg within the normal
range of 300-1000 ng/dL on Day 112. In patients treated with AndroGel 1.62%,
81.6% (146/179) had Cavg within the normal range at Day 112. The secondary endpoint
was the percentage of patients, with Cmax above three pre-determined limits.
The percentages of patients with Cmax greater than 1500 ng/dL, and between 1800
and 2499 ng/dL on Day 112 were 11.2% and 5.5%, respectively. Two patients had
a Cmax > 2500 ng/dL on Day 112 (2510 ng/dL and 2550 ng/dL, respectively);
neither of these 2 patients demonstrated an abnormal Cmax on prior or subsequent
assessments at the same dose.

Patients could agree to continue in an open-label, active treatment maintenance
period of the study for an additional 182 days.

Dose titrations on Days 14, 28, and 42 resulted in final doses of 20.25 mg
– 81 mg on Day 112 as shown in Table 5.

Table 5: Mean (SD) Testosterone Concentrations (Cavg and
Cmax) by final dose on Days 112 and 364

Parameter

Final Dose on Day 112

Placebo
(n=27)

20.25 mg
(n=12)

40.5 mg
(n=34)

60.75 mg
(n=54)

81 mg
(n=79)

All Active
(n=179)

Cavg (ng/dL)

303 (135)

457 (275)

524 (228)

643 (285)

537 (240)

561 (259)

Cmax (ng/dL)

450 (349)

663 (473)

798 (439)

958 (497)

813 (479)

845 (480)

Final Dose on Day 364

20.25 mg
(n=7)

40.5 mg
(n=26)

60.75 mg
(n=29)

81 mg
(n=74)

Continuing Active
(n=136)

Cavg (ng/dL)

386 (130)

474 (176)

513 (222)

432 (186)

455 (192)

Cmax (ng/dL)

562 (187)

715 (306)

839 (568)

649 (329)

697 (389)

Figure 3 summarizes the pharmacokinetic profile of total testosterone in patients
completing 112 days of AndroGel 1.62% treatment administered as a starting dose
of 40.5 mg of testosterone (2 pump actuations) for the initial 14 days followed
by possible titration according to the follow-up testosterone measurements.

Efficacy was maintained in the group of men that received AndroGel 1.62% for
one full year. In that group, 78% (106/136) had average serum testosterone concentrations
in the normal range at Day 364. Figure 4 summarizes the mean total testosterone
profile for these patients on Day 364.

The mean estradiol and DHT concentration profiles paralleled the changes observed
in testosterone. The levels of LH and FSH decreased with testosterone treatment.
The decreases in levels of LH and FSH are consistent with reports published
in the literature of long-term treatment with testosterone.

Last reviewed on RxList: 6/8/2011
This monograph has been modified to include the generic and brand name in many instances.